Cystic Fibrosis (CF), the most common recessive disease among Caucasians, is caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a cAMP-activated chloride ion channel. CF patients develop chronic lung infection and inflammation, which can be mediated in part by interleukin (IL)-17A leading to bronchiectasis, and ultimately respiratory failure and death. CF shares features with many other forms of lung disease where inflammation plays a major role. Ninety percent of CF patients carry at least one copy of the ?F508 allele. Current treatment for CF lung disease is only marginally effective in CF patients with the ?F508 mutation. A key limitation is that most CF patients produce high levels of Transforming Growth Factor (TGF)-?1. Our published work has shown that TGF-?1 represses ?F508-CFTR transcription in HBE cells, acting upstream of the therapeutic agent VX-809 and thus blocks its efficacy. High TGF-?1 levels also prime CF patients for inflammation. Thus, TGF-?1 signaling is a major endogenous pathway limiting the efficacy of VX-809 in CF in addition to promoting inflammation. Our preliminary data confirm that VX-809 reverses neither the TGF-?1 inhibition of CFTR transcription nor the IL-17A induced secretion of inflammatory cytokines. TGF-?1 has many homeostatic effects, including would healing and T-cell differentiation. Currently it is unknown how to precisely target the pathogenic effects of TGF-?1 without compromising the homeostatic function. Targeting the cell-type specific and disease-relevant activators in the TGF-?1 pathway could serve as a novel therapeutic strategy to selectively eliminate the pathogenic sequels of TGF-?1 in CF. We have shown that Dab2 (disabled-2) may play such role acting downstream of TGF-?1 receptors, and directing nuclear trafficking of a key mediator in TGF-?1 pathway, Smad3 in human bronchial epithelial (HBE) cells. Our central hypothesis is that TGF-?1 stabilizes the Dab2-Smad3 interaction to increase nuclear delivery of Smad3 leading to repression of ?F508-CFTR transcription and inflammation in HBE cells. Dab2 favors Smad3 signaling, blocks ?F508-CFTR protein rescue by VX-809, feeds the pro-inflammatory cross-talk, and worsens outcomes. The Dab2-Smad3 interface thus represents a novel therapeutic target for CF and for other forms of lung disease where inflammation is mediated by TGF-?1. In aim 1, we will test the hypothesis that Dab2 and Smad3 mediate the pathogenic effects of TGF-?1 in HBE cells. In aim 2 test the hypothesis that Dab2 directs nuclear translocation of activated Smad3 specifically in HBE cells. In aim 3 we will test the hypothesis that a Dab2?Smad3 interaction is required for the pathogenic effects of TGF-?1 in HBE cells. We anticipate that our studies will lead to novel therapy precisely targeting the pathogenic TGF-?1 activity, to preserve airway integrity, and to promote efficacy of correctors to restore the ?F508-CFTR function in CF patients. Our studies will also benefit many other patients with common non-CF lung disease.